Novel nitric oxide donors are coronary vasodilators that also bind to the papain-like protease of SARS-CoV-2

Several investigational nitric oxide donors were originally created to correct vascular endothelial dysfunction in cardiovascular diseases. These 48 compounds contain an urea-like moiety attached to the well-known NO donors isosorbide 2- and 5-mononitrate. CR-0305 and CR-0202 were synthesized and fo...

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Veröffentlicht in:Biomedicine & pharmacotherapy 2024-04, Vol.173, p.116378-116378, Article 116378
Hauptverfasser: Schmedtje, John F., Ciske, Fred, Muzzarelli, Kendall M., Assar, Zahra
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Sprache:eng
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Zusammenfassung:Several investigational nitric oxide donors were originally created to correct vascular endothelial dysfunction in cardiovascular diseases. These 48 compounds contain an urea-like moiety attached to the well-known NO donors isosorbide 2- and 5-mononitrate. CR-0305 and CR-0202 were synthesized and found to be nontoxic in the cell lines HMEC-1, A549/hACE2 and VeroE6. CR-0305 induced vasodilation in human coronary arteries ex vivo. Since NO can also have antiviral properties, a study of drug-protein interactions with SARS-CoV-2 was undertaken using in silico modeling. CR-0305 experimentally outperformed the other compounds, including CR-0202, in binding the catalytic site of SARS-CoV-2 papain-like protease (PLpro). PLpro is a primary target for therapeutic inhibition of SARS-CoV-2 as it mediates viral replication and modulates host innate immune responses. CR-0305 is predicted to sit firmly in the PLpro catalytic pocket as confirmed by molecular dynamics simulations, wherein stability of binding to the catalytic site of PLpro induces a conformational change in the BL2 loop to a more closed conformation as observed previously with GRL0617. Surface plasmon resonance was performed with CR-0305 and CR-0202 to characterize binding affinity to purified SARS-CoV-2 PLpro protein. CR-0305 and CR-0202 also inhibited SARS-CoV-2 infection compared to vehicle as measured by virus N protein staining with a specific antibody in A549-ACE2 and VeroE6 cells at 20 µM. CR-0305 is a coronary vasodilator that appears to bind to the catalytic site of the PLpro of SARS-CoV-2 while targeting delivery of antiviral NO to cells infected by SARS-CoV-2, suggesting multiple indications for future development. •The nitric oxide donor CR-0305, binds the catalytic site of SARS-CoV-2 papain-like protease.•PLpro is a primary target for therapeutic inhibition of SARS-CoV-2.•CR-0305 is a coronary vasodilator that may target delivery of NO to cells infected by SARS-CoV-2.
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2024.116378